Background: HTLV-1 causes proliferation of clonal populations of infected T cells in vivo, each clone defined by a
unique proviral integration site in the host genome. The proviral load is strongly correlated with odds of the
inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is evidence that
asymptomatic HTLV-1 carriers (ACs) have a more effective CD8 + T cell response, including a higher frequency of
HLA class I alleles able to present peptides from a regulatory protein of HTLV-1, HBZ. We have previously shown
that specific features of the host genome flanking the proviral integration site favour clone survival and spontaneous
expression of the viral transactivator protein Tax in naturally infected PBMCs ex vivo. However, the previous studies were
not designed or powered to detect differences in integration site characteristics between ACs and HAM/TSP patients.
Here, we tested the hypothesis that the genomic environment of the provirus differs systematically between ACs and
HAM/TSP patients, and between individuals with strong or weak HBZ presentation.
Methods: We used our recently described high-throughput protocol to map and quantify integration sites in 95 HAM/
TSP patients and 68 ACs from Kagoshima, Japan, and 75 ACs from Kumamoto, Japan. Individuals with 2 or more HLA
class I alleles predicted to bind HBZ peptides were classified ‘strong’ HBZ binders; the remainder were classified ‘weak
binders’.
Results: The abundance of HTLV-1-infected T cell clones in vivo was correlated with proviral integration in genes and
in areas with epigenetic marks associated with active regulatory elements. In clones of equivalent abundance, integration
sites in genes and active regions were significantly more frequent in ACs than patients with HAM/TSP, irrespective
of HBZ binding and proviral load. Integration sites in genes were also more frequent in strong HBZ binders than weak
HBZ binders.
Conclusion: Clonal abundance is correlated with integration in a transcriptionally active genomic region, and these
regions may promote cell proliferation. A clone that reaches a given abundance in vivo is more likely to be integrated
in a transcriptionally active region in individuals with a more effective anti-HTLV-1 immune response, such those who
can present HBZ peptides or those who remain asymptomatic.